While a sterilizing cure of HIV-1 infection has only been reported in a single patient after a stem cell transplant with CCR5D32 homozygous cells, a spontaneous functional cure of HIV-1 occurs in 0.3-0.5% of all infected persons. These individuals, termed elite controllers (EC), maintain undetectable levels of HIV-1 replication in th absence of treatment, despite the repeated isolation of replication-competent virus from their serum. In this way, these individuals provide living evidence that immune-mediated control of HIV-1 infection is possible, and the identification of effective immune defense mechanisms that are active in these patients holds promise for inducing a functional cure of HIV-1 infection in a broader HIV-1 patient population. Previously, the analysis of such mechanisms has mostly focused on studying individual components of the immune system in an isolated fashion, yet, it is now increasingly clear that effective immune defense programs in these patients are likely to involve complex networks of innate and adaptive immune responses and that integrative, iterative analysis steps will be required to mechanistically understand synergistic networks of immune defense in EC. Yet, such integrated programs of immune control can hardly be detected using traditional reductionist approaches that are biased towards specific pre-defined molecules or investigate one specific aspect of immune defense in an isolated fashion. Here, we will employ a multi-step research strategy to identify comprehensive, multi-system programs of immune defense in EC and explore their underlying functional mechanisms. In Specific Aim 1, we will use novel, high throughput technologies such as genome-wide SNP analysis and multiplexed mRNA and miRNA expression analysis in sorted leukocellular subsets in combination with multidimensional immunologic assays to identify molecular signatures that define effective innate and adaptive HIV-1 immune responses in EC. Using biocomputational algorithms, we will be able to detect connectivity between various aspects of immune defense mechanisms, and identify programs that link gene expression, immune responses and clinical development of EC phenotype. In Specific Aim 2, we will validate these identified patterns of immune control by testing their predictive power in alternative natural-history HIV-1 patient cohorts; these studies will allow to identify a set of validated immune defense parameters that can significantly influence HIV- 1 disease outcome, and may represent possible targets for interventional approaches. By investigating, validating and mechanistically exploring HIV-1 immune responses in EC in relationship to genetic variation and mRNA/miRNA expression profiles, the proposed studies will generate unprecedented insights into effective mechanisms of HIV-1 immune control, and may lead to novel clinical strategies to induce a functional cure of HIV-1 in a broader patient population.